Combination therapy with syk kinase inhibitor

Abstract

The invention encompasses methods of increasing platelet levels in a patient having or at risk for immune thrombocytopenia comprising co-administering a Syk kinase inhibitor and a thrombopoietin receptor agonist, and methods of treating thrombocytopenia comprising co-administering a Syk kinase inhibitor and a thrombopoietin receptor agonist to a patient in need thereof, as well as pharmaceutical compositions for use in these methods.

1 . A method of increasing platelet levels in a patient having or at risk for immune thrombocytopenia comprising co-administering:
 (a) a Syk kinase inhibitor; and   (b) a thrombopoietin receptor agonist.   
     
     
         2 . The method of  claim 1 , wherein the Syk kinase inhibitor is a 2,4-pyrimidinediamine compound of formula I: 
       
         
           
           
               
               
           
         
       
       a salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 L 1  and L 2 , independently of each other, are selected from the group consisting of a direct bond, a (C1-C3) alkylene optionally substituted with one or more of the same or different R 9  groups, and 1-3 membered heteroalkyldiyl optionally substituted with one or more of the same or different R 9  groups; 
 R 2  is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered heterocyclyl optionally substituted with one or more of the same or different R 8  groups, (C5-C15) aryl optionally substituted with one or more of the same or different R 8  groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 4  is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered heterocyclyl optionally substituted with one or more of the same or different R 8  groups, (C5-C15) aryl optionally substituted with one or more of the same or different R 8  groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 5  is selected from the group consisting of R 6 , (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, and (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups; 
 each R 6 , independently of the others, is selected from the group consisting of hydrogen, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c R c , halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O) R d , —OS(O) 2 Rd, —OS(O) 2 OR d , —OS(O)NR c R c , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —OC(O)R d , —SC(O)R d , —OC(O)OR d , —SC(O)OR d , —OC(O)NR c R c , —SC(O)NR c R c , —OC(NH)NR c R c , —SC(NH)NR c R c , —[NHC(O)] n R d , —[NHC(O)] n OR d , —[NHC(O)] n R c R c , —[NHC(NH)] n R c R c , (C5-C10) aryl optionally substituted with one or more of the same or different R 8  groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R 8  groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups, and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R 8  groups; 
 R 8  is selected from the group consisting of R e , R b , R e  substituted with one or more of the same or different R a  or R b , —OR a  substituted with one or more of the same or different R a  or R b , —B(OR a ) 2 , —B(NR c R c ) 2 , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —O—(CHR a ) m —R b , —O—(CH 2 ) m —CH[(CH 2 ) m R b ]R b , —S—(CHR a ) m —R b , —C(O)NH—(CH 2 ) m —R b , —C(O)NH—(CHR a ) m —R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —S—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —S—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , —N[(CH 2 ) m R b ] 2 , —NH—C(O)—NH—(CH 2 ) m —R b , —NH—C(O)—(CH 2 ) m —CHR b R b  and —NH—(CH 2 ) m —C(O)—NH—(CH 2 ) m —R b ; 
 each R 9 , independently of the others, is selected from the group consisting of (C1-C6) alkyl, —OR a , —C(O)OR a , (C5-C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, and 5-10 membered heteroaryl optionally substituted with one or more of the same or different halogens; 
 each R a , independently of the others, is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-11 membered heterocyclylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each R b , independently of the others, is a suitable group selected from the group consisting of ═O, —OR d , (C1-C3) haloalkyloxy, ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , S(O) 2 OR c , S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  and —[NR a C(NR a )] n NR c R c ; 
 each R c , independently of the others, is a progroup or R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  or suitable R b  groups; 
 each R d , independently of the others, is a progroup or R a ; 
 each R e , independently of the others, is selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each m, independently of the others, is an integer from 1 to 3; and 
 each n, independently of the others, is an integer from 0 to 3. 
 
     
     
         3 . The method of  claim 1 , wherein the Syk kinase inhibitor is a compound of formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or N-oxide thereof, wherein
 X is selected from the group consisting of N and CH; 
 Y is selected from the group consisting of O, S, SO, SO 2 , SONR 41 , NH, and NR 42 ; 
 Z is selected from the group consisting of O, S, SO, SO 2 , SONR 41 , NH, and NR 42 ; 
 each R 41 , independently of the others, is hydrogen or lower alkyl; 
 each R 42 , independently of the others, is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, and —(CRR) n —R p , wherein 
 each R, independently of the others, is selected from the group consisting of hydrogen, lower alkyl and halo; 
 n is an integer from 0 to 4; and 
 R p  is selected from the group consisting of phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphonamidate, and cyclic phosphonamidate; 
 each R 43 , independently of the others, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, and halo, or, alternatively, two R 43  bonded to the same carbon atom are taken together to form an oxo (═O), ═NH or ═NR 44  group and the other two R 43  are as defined above; 
 each R 44 , independently of the others, is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl; and 
 R 45  is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl. 
 
     
     
         4 . The method of  claim 3 , wherein two R 43  bonded to the same carbon atom are taken together to form an oxo (═O) group and the other two R 43  independently of one another are hydrogen or alkyl. 
     
     
         5 . The method of  claim 3 , wherein X is N. 
     
     
         6 . The method of  claim 3 , wherein each R 41  is methyl. 
     
     
         7 . The method of  claim 3 , wherein Y is O and Z is NH or NR 42 . 
     
     
         8 . The method of  claim 7 , wherein Z is NR 42  and R 42  is —(CRR) n —R p . 
     
     
         9 . The method of  claim 8 , wherein n is one. 
     
     
         10 . The method of  claim 9 , wherein each R is hydrogen and R p  is phosphate or phosphate ester. 
     
     
         11 . The method of  claim 1 , wherein the thrombopoietin receptor agonist is a polypeptide. 
     
     
         12 . The method of  claim 11 , wherein the polypeptide is thrombopoietin. 
     
     
         13 . The method of  claim 11 , wherein the polypeptide comprises the sequence Ile-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Trp-Leu-Ala-Ala-Arg-Ala (SEQ ID NO: 1). 
     
     
         14 . The method of  claim 11 , wherein the polypeptide is AMG531. 
     
     
         15 . The method of  claim 1 , wherein the thrombopoietin receptor agonist is a small molecule. 
     
     
         16 . The method of  claim 15 , wherein the small molecule is 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-di-hydropyrazol-4-ylidene]hydrazine}-2′-hydroxybiphenyl-3-carboxylic acid, or a pharmaceutically acceptable salt or ester thereof. 
     
     
         17 . The method of  claim 15 , wherein the small molecule is eltrombopag. 
     
     
         18 . The method of  claim 1 , wherein the immune thrombocytopenia is immune thrombocytopenia purpura. 
     
     
         19 . A method of treating thrombocytopenia comprising co-administering to a patient in need thereof a Syk kinase inhibitor and a thrombopoietin receptor agonist. 
     
     
         20 . The method of  claim 19 , wherein the Syk kinase inhibitor is a 2,4, pyrimidinediamine compound of formula I: 
       
         
           
           
               
               
           
         
       
       a salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 L 1  and L 2 , independently of each other, are selected from the group consisting of a direct bond, a (C1-C3) alkylene optionally substituted with one or more of the same or different R 9  groups, and 1-3 membered heteroalkyldiyl optionally substituted with one or more of the same or different R 9  groups; 
 R 2  is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered heterocyclyl optionally substituted with one or more of the same or different R 8  groups, (C5-C15) aryl optionally substituted with one or more of the same or different R 8  groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 4  is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered heterocyclyl optionally substituted with one or more of the same or different R 8  groups, (C5-C15) aryl optionally substituted with one or more of the same or different R 8  groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 5  is selected from the group consisting of R 6 , (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, and (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups; 
 each R 6 , independently of the others, is selected from the group consisting of hydrogen, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c R c , halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 Rd, —OS(O) 2 R d , —OS(O)NR c R c , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —OC(O)R d , —SC(O)R d , —OC(O)OR d , —SC(O)OR d , —OC(O)NR c R c , —SC(O)NR c R c , —OC(NH)NR c R c , —SC(NH)NR c R c , —[NHC(O)] n R d , —[NHC(O)] n OR d , —[NHC(O)] n R c R c , —[NHC(NH)] n R c R c , (C5-C10) aryl optionally substituted with one or more of the same or different R 8  groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R 8  groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups, and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R 8  groups; 
 R 8  is selected from the group consisting of R e , R b , R e  substituted with one or more of the same or different R a  or R b , —OR a  substituted with one or more of the same or different R a  or R b , —B(OR a ) 2 , —B(NR c R c ) 2 , —(CH 2 ) m R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —O—(CHR a ) m —R b , —O—(CH 2 ) m —CH[(CH 2 ) m R b ]R b , —S—(CHR a ) m —R b , —C(O)NH—(CH 2 ) m —R b , —C(O)NH—(CHR a ) m —R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —S—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —S—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , —N[(CH 2 ) m R b ] 2 , —NH—C(O)—NH—(CH 2 ) m —R b , —NH—C(O)—(CH 2 ) m —CHR b R b  and —NH—(CH 2 ) m —C(O)—NH—(CH 2 ) m —R b ; 
 each R 9 , independently of the others, is selected from the group consisting of (C1-C6) alkyl, —OR a , —C(O)OR a , (C5-C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, and 5-10 membered heteroaryl optionally substituted with one or more of the same or different halogens; 
 each R a , independently of the others, is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-11 membered heterocyclylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each R b , independently of the others, is a suitable group selected from the group consisting of ═O, —OR d , (C1-C3) haloalkyloxy, ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , S(O) 2 OR c , S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 OR d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  and —[NR a C(NR a )] n NR c R c ; 
 each R c , independently of the others, is a progroup or R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  or suitable R b  groups; 
 each R d , independently of the others, is a progroup or R a ; 
 each R e , independently of the others, is selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each m, independently of the others, is an integer from 1 to 3; and 
 each n, independently of the others, is an integer from 0 to 3. 
 
     
     
         21 . The method of  claim 19 , wherein the Syk kinase inhibitor is a 2,4-pyrimidinediamine compound of formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or N-oxide thereof, wherein
 X is selected from the group consisting of N and CH; 
 Y is selected from the group consisting of O, S, SO, SO 2 , SONR 41 , NH, and NR 42 ; 
 Z is selected from the group consisting of O, S, SO, SO 2 , SONR 41 , NH, and NR 42 ; 
 each R 41 , independently of the others, is hydrogen or lower alkyl; 
 each R 42 , independently of the others, is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, and —(CRR) n —R p , wherein
 each R p , independently of the others, is selected from the group consisting of hydrogen, lower alkyl and halo; 
 n is an integer from 0 to 4; and 
 R p  is selected from the group consisting of phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphonamidate, and cyclic phosphonamidate; 
 
 each R 43 , independently of the others, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, and halo, or, alternatively, two R 43  bonded to the same carbon atom are taken together to form an oxo (═O), ═NH or ═NR 44  group and the other two R 43  are as defined above; 
 each R 44 , independently of the others, is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl; and 
 R 45  is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl. 
 
     
     
         22 . A pharmaceutical composition comprising a Syk kinase inhibitor and a thrombopoietin receptor agonist. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the Syk kinase inhibitor is a 2,4-pyrimidinediamine compound of formula I 
       
         
           
           
               
               
           
         
       
       a salt, hydrate, solvate, N-oxide or prodrug thereof, wherein:
 L 1  and L 2 , independently of each other, are selected from the group consisting of a direct bond, a (C1-C3) alkylene optionally substituted with one or more of the same or different R 9  groups, and 1-3 membered heteroalkyldiyl optionally substituted with one or more of the same or different R 9  groups; 
 R 2  is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered heterocyclyl optionally substituted with one or more of the same or different R 8  groups, (C5-C15) aryl optionally substituted with one or more of the same or different R 8  groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 4  is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups, 3-8 membered heterocyclyl optionally substituted with one or more of the same or different R 8  groups, (C5-C15) aryl optionally substituted with one or more of the same or different R 8  groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups; 
 R 5  is selected from the group consisting of R 6 , (C2-C6) alkenyl optionally substituted with one or more of the same or different R 8  groups, (C2-C6) alkynyl optionally substituted with one or more of the same or different R 8  groups, and (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R 8  groups; 
 each R 6 , independently of the others, is selected from the group consisting of hydrogen, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c R c , halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O)NR c R c , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —OC(O)R d , —SC(O)R d , —OC(O)OR d , —SC(O)OR d , —OC(O)NR c R c , —SC(O)NR c R c , —OC(NH)NR c R c , —SC(NH)NR c R c , —[NHC(O)] n R d , —[NHC(O)] n OR d , —[NHC(O)] n R c R c , —[NHC(NH)] n R c R c , (C5-C10) aryl optionally substituted with one or more of the same or different R 8  groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R 8  groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 8  groups, and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R 8  groups; 
 R 8  is selected from the group consisting of R e , R b , R e  substituted with one or more of the same or different R a  or R b , —OR a  substituted with one or more of the same or different R a  or R b , —B(OR a ) 2 , —B(NR c R c ) 2 , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , —O—CHR a R b , —O—CR a (R b ) 2 , —O—(CHR a ) m —R b , —O—(CH 2 ) m —CH[(CH 2 ) m R b ]R b , —S—(CHR a ) m —R b , —C(O)NH—(CH 2 ) m —R b , —C(O)NH—(CHR a ) m —R b , —O—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —S—(CH 2 ) m —C(O)NH—(CH 2 ) m —R b , —O—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —S—(CHR a ) m —C(O)NH—(CHR a ) m —R b , —NH—(CH 2 ) m —R b , —NH—(CHR a ) m —R b , —N[(CH 2 ) m R b ] 2 , —NH—C(O)—NH—(CH 2 ) m —R b , —NH—C(O)—(CH 2 ) m —CHR b R b  and —NH—(CH 2 ) m —C(O)—NH—(CH 2 ) m —R b ; 
 each R 9 , independently of the others, is selected from the group consisting of (C1-C6) alkyl, —OR a , —C(O)OR a , (C5-C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, and 5-10 membered heteroaryl optionally substituted with one or more of the same or different halogens; 
 each R a , independently of the others, is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-11 membered heterocyclylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each R b , independently of the others, is a suitable group selected from the group consisting of ═O, —OR d , (C1-C3) haloalkyloxy, ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR c , S(O)NR c R c , S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  and —[NR a C(NR a )] n NR c R c ; 
 each R c , independently of the others, is a progroup or R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  or suitable R b  groups; 
 each R d , independently of the others, is a progroup or R a ; 
 each R e , independently of the others, is selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; 
 each m, independently of the others, is an integer from 1 to 3; and 
 each n, independently of the others, is an integer from 0 to 3. 
 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the Syk kinase inhibitor is a 2,4-pyrimidinediamine compound of formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or N-oxide thereof, wherein
 X is selected from the group consisting of N and CH; 
 Y is selected from the group consisting of O, S, SO, SO 2 , SONR 41 , NH, and NR 42 ; 
 Z is selected from the group consisting of O, S, SO, SO 2 , SONR 41 , NH, and NR 42 ; 
 each R 41 , independently of the others, is hydrogen or lower alkyl; 
 each R 42 , independently of the others, is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, and —(CRR) n —R p , wherein
 each R, independently of the others, is selected from the group consisting of hydrogen, lower alkyl and halo; 
 n is an integer from 0 to 4; and 
 R p  is selected from the group consisting of phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphonamidate, and cyclic phosphonamidate; 
 
 each R 43 , independently of the others, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, and halo, or, alternatively, two R 43  bonded to the same carbon atom are taken together to form an oxo (═O), ═NH or ═NR 44  group and the other two R 43  are as defined above; 
 each R 44 , independently of the others, is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl; and 
 R 45  is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.